WO1996002245A1 - Nitric oxide synthase inhibitors for inhibiting the production of airway mucus - Google Patents
Nitric oxide synthase inhibitors for inhibiting the production of airway mucus Download PDFInfo
- Publication number
- WO1996002245A1 WO1996002245A1 PCT/GB1995/001657 GB9501657W WO9602245A1 WO 1996002245 A1 WO1996002245 A1 WO 1996002245A1 GB 9501657 W GB9501657 W GB 9501657W WO 9602245 A1 WO9602245 A1 WO 9602245A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- mammal
- production
- synthase inhibitor
- mucus
- airway mucus
- Prior art date
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to the use of nitric oxide synthase inhibitors in inhibiting secretion and/or production of airway mucus, in particular in treating chronic bronchitis, cystic fibrosis and bronchorrhea.
- cystic fibrosis In cystic fibrosis several functions of airway epithelia are abnormal including thickened airway surface fluid. This thickened airway fluid contributes to the recurrent pulmonary infections and loss of ventilatory function that occur in cystic fibrosis. Retained airway secretions are also known to contribute to the morbidity of other pulmonary diseases such as asthma and chronic obstructive pulmonary disease.
- the therapeutic goal in cystic fibrosis and other pulmonary diseases in which the water content of the mucus is altered is to remove retained secretions from the lungs.
- the use of aerosolised amiloride to facilitate the removal of retained mucus secretions is described in U.S. Patent No. 4,501,729. Amiloride appears to block Na + reabsorption by airway epithelial cells, and therefore inhibits water absorption from mucus.
- a different therapeutic approach is to increase the water content of the airway surface liquid by modulating the activity of chloride channels.
- An example of this is the administration of ATP or UTP, which appear to induce hydrated mucus secretions by stimulating chloride secretion from respiratory epithelial cells. See, e.g., C. Stock, Breathing Easier: A promising Treatment for Cystic Fibrosis, Endeavors, 10, 10-11 (Fall 1992) (Published by the Office of Research Services, The University of North Carolina at Chapel Hill).
- nitric oxide synthase inhibitor is beneficial in inhibiting the production and/or secretion of airway mucus.
- the present invention provides a method of inhibiting the production and/or secretion of airway mucus which comprises administering to a mammal in need thereof an effective amount of an NO synthase inhibitor to the lungs of the mammal.
- the present invention provides a method of combating cystic fibrosis which comprises administering to a mammal in need thereof an effective amount of an NO synthase inhibitor to the mammal.
- the present invention provides a method of combating excessive mucus production in chronic bronchitis which comprises administering to a mammal in need thereof an effective amount of an NO synthase inhibitor to the mammal.
- the present invention provides a method of combating emphysema which comprises administering to a mammal in need thereof an effective amount of an NO synthase inhibitor to the mammal.
- the method of the present invention may further comprise the step of concurrently administering a further active agent useful in improving mucociliary clearance of airway mucus, for example a sodium channel blocker, such as amiloride, in an amount effective to inhibit the reabsorption of water from lung mucus secretions, or a lantibiotic such as duramycin, or a nucleotide such as adenosine triphosphate (ATP) or uridine triphosphate (UTP) in an amount effective to facilitate hydration and clearance of airway mucus.
- a sodium channel blocker such as amiloride
- ATP adenosine triphosphate
- UDP uridine triphosphate
- the present invention also provides the use of an NO synthase inhibitor for the manufacture of a medicament for the inhibition of the production of airway mucus in a patient in need of such treatment.
- the patient is suffering from cystic fibrosis or chronic bronchitis.
- the NO synthase inhibitor is an arginine derivative such as those described in U.S. Patent 5028627 and preferably it is N G -monoethyl-L-arginine (L-NMMA) or a salt thereof.
- L-NMMA N G -monoethyl-L-arginine
- L-NMMA is available from Sigma Chemical Company Limited, Fancy Road, Poole, Dorset BH17 7NH, England.
- NO synthase inhibitors for example L-NMMA
- the present invention includes NO synthase inhibitors in the form of salts, in particular acid addition salts.
- Suitable salts include those formed with both organic and inorganic acids.
- acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question.
- preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, p-toluenesulphonic, benzenesulphonic and isethionic acids.
- Salts of the compounds of NO-synthase inhibitors can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
- the present invention provides a pharmaceutical formulation comprising the NO synthase inhibitor or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers therefor and optionally one or more other therapeutic ingredients.
- the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- the formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), intranasal, inhaled, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient.
- the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the NO-synthase inhibitor or a pharmaceutically acceptable salt or solvate thereof ("active ingredient”) with the carrier which constitutes one or more accessory ingredients.
- active ingredient a pharmaceutically acceptable salt or solvate thereof
- the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
- Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.
- the active ingredient may also be presented as a bolus, electuary or paste.
- a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
- Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent.
- Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
- the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
- Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
- the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use.
- Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
- Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
- Formulations for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
- Formulations suitable for pulmonary administration via the buccal cavity are presented such that particles containing the active ingredient and desirably having a diameter in the range 0.5 to 7 microns are delivered into the bronchial tree of the recipient.
- Such formulations may be in the form of finely comminuted powders which may conveniently be presented in a pierceable capsule, for example of gelatin, for use in an inhalation device, or as a self-propelling formulation (also referred to as an aerosol formulation) comprising the active ingredient a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactant and/or a solid diluent.
- suitable liquid propellants include propane and the chlorofluorocarbons
- suitable gaseous propellants include carbon dioxide.
- Suitable surfactants include sorbitan trioleate (which is available for example under the trade name "Arlacel 85”), Polysorbate 20 and oleic acid.
- Self- propelling formulations may also be employed wherein the active ingredient is dispensed in the form of droplets of solution or suspension.
- the self-propelling formulation typically contains from 0.05 to 20mg/ml e.g. 0.1 to 5mg/ml of the active ingredient.
- Such self-propelling formulations are analogous to those known in the art and may be prepared by established procedures. Suitably they are presented in a container provided with either a manually-operable or automatically functioning valve having the desired spray characteristics; advantageously the valve is of a metered type delivering a fixed volume, for example, 25 to 100 microlitres, upon each operation thereof.
- the active ingredient may be in the form of a solution or suspension for use in an atomiser or nebuliser whereby an accelerated airstream or ultrasonic agitation is employed to produce a fine droplet mist for inhalation.
- solutions or suspensions may comprise, in addition to the naphthoquinone and solvent(s), optional ingredients such as surfactants. Suitable surfactants include those described above for self-propelling formulations.
- the solution or suspension typically contains from 500 ⁇ M to lOOmM e.g. 0.5mM to 25mM of the active ingredient. When a suspension of the active ingredient is employed, this compound is preferably in finely divided form, e.g. in micronised form.
- Formulations suitable for nasal administration include presentations generally similar to those described above for pulmonary administration. When dispensed such formulations should desirably have a particle diameter in the range 10 to 200 microns to enable retention in the nasal cavity; this may be achieved by, as appropriate, use of a powder of a suitable particle size or choice of an appropriate valve. Other suitable formulations include coarse powders having a particle diameter in the range 20 to 500 microns, for administration by rapid inhalation through the nasal passage from a container held close up to the nose, and nasal drops comprising 0.2 to 5% w/v of the active ingredient in aqueous or oily solution or suspension.
- Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
- formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
- the NO synthase inhibitors of the invention may be administered orally, or via injection at a dose of from 1 to lOOmg/kg per day.
- a dose of from 1 to lOOmg/kg per day When the NO synthase inhibitors are given by injection, this will normally be in the form of an intravenous bolus or by infusion, preferably the latter.
- the dose range for adult humans is generally from 70mg to 2.5g/day and preferably 150mg to 2g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5mg to 500mg, usually around lOmg to 200mg.
- the NO synthase inhibitors are administered by aerosol to the lungs of a subject in an amount sufficient to achieve concentrations of NO synthase inhibitor on the airway surface liquid of the patient of about 5 ⁇ Moles/litre to 1000 ⁇ Moles/litre, preferably 100 ⁇ Moles/litre to 500 ⁇ Moles/litre.
- the dose of the NO synthase inhibitor will vary according to the potency of the inhibitor, its selectivity for the different forms of the enzyme and the dose at which adverse pharmacological effects become evident.
- the person skilled in the art will take these factors into account when determining the dose of inhibitor to be administered.
- the present invention will now be described by way of example only.
- the experimental mode used is the SPOC-1 cell line, a mucin-secreting cell line that results from a spontaneous transformation in a primary culture of rat tracheal cells.
- SPOC-1 cells seeded in a rat tracheal xenograft and implanted into a nude mouse differentiate into a pseudo-stratified epithelium in which the upper layer of cells possesses a goblet cell phenotype, including the possession of 1 + ⁇ m granules.
- the cells In culture either on plastic or on Transwell-Col (Costar) permeable supports, the cells differentiate over a period of 9 to 12 days into a multilayered (3 to 4 layers) epithelium in which outer layers contain material which stains positive with PAS.
- a PAS-positive glycoconjugate with a molecular weight appropriate for mucin is detected by gel electrophoresis of SPOC cell lysate and perfiisate; and SPOC cells stain positive with an monoclonal antibody specific to purified rat mucin.
- SPOC-1 cells grown on plastic are employed as a convenient experimental model to test chemical compounds for inhibitory or stimulatory effects on mucin secretion.
- Each compound is initially tested, on duplicate cultures in short-term exposures, for potential effects on both baseline and ATP-stimulated secretion over a range of 12 doses (including a control).
- 12-well plates are perfused (each well independently), and after a suitable equilibration period, 5 min fractions collected for baseline (30 min), baseline + test compound (60 min), and ATP + test compound (60 min).
- a level of ATP at its EC 50 , lO ⁇ M is used, so potential stimulatory effects on regulated mucin secretion are detected with the compounds of interest; if the primary interest is in the inhibitory direction, then a maximal ATP dose, 100 or 300 ⁇ M is used.
- the fractions collected are assessed for mucin content by ELLA, and the data analysed as follows, using standard spreadsheet software (MS Excel). Data from duplicate samples is averaged.
- the time course of mucin secretion for each perfused culture is plotted, and the levels of mucin secretion assessed for each period (baseline, baseline + compound, and compound + ATP). Calculating the data relative to baseline rates, dose- response curves for the baseline + compound and the compound +ATP periods are constructed. These plots are analysed for inhibitory or stimulatory effects by the compounds of interest, by comparing data for each baseline + compound period to the preceding baseline, and for each compound + ATP period to the preceding baseline + compound period.
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Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/765,547 US5859058A (en) | 1994-07-14 | 1995-07-13 | Nitric oxide synthase inhibitors for inhibiting the production of airway mucas |
JP8504808A JPH10502662A (en) | 1994-07-14 | 1995-07-13 | Nitric oxide synthase inhibitor suppresses airway mucus formation |
EP95924472A EP0768875A1 (en) | 1994-07-14 | 1995-07-13 | Nitric oxide synthase inhibitors for inhibiting the production of airway mucus |
AU28966/95A AU2896695A (en) | 1994-07-14 | 1995-07-13 | Nitric oxide synthase inhibitors for inhibiting the production of airway mucus |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US27516794A | 1994-07-14 | 1994-07-14 | |
US275,167 | 1994-07-14 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996002245A1 true WO1996002245A1 (en) | 1996-02-01 |
Family
ID=23051153
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1995/001657 WO1996002245A1 (en) | 1994-07-14 | 1995-07-13 | Nitric oxide synthase inhibitors for inhibiting the production of airway mucus |
Country Status (5)
Country | Link |
---|---|
US (1) | US5859058A (en) |
EP (1) | EP0768875A1 (en) |
JP (1) | JPH10502662A (en) |
AU (1) | AU2896695A (en) |
WO (1) | WO1996002245A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6274593B1 (en) | 1997-05-01 | 2001-08-14 | Smithkline Beecham P.L.C. | Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors |
US6620848B2 (en) * | 1997-01-13 | 2003-09-16 | Smithkline Beecham Corporation | Nitric oxide synthase inhibitors |
WO2005041975A1 (en) * | 2003-10-31 | 2005-05-12 | Altana Pharma Ag | Use of bh4 for the treatment of respiratory diseases |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4194364B2 (en) * | 2000-10-16 | 2008-12-10 | デューク・ユニバーシティ | Therapeutic use of aerosolized S-nitrosoglutathione in cystic fibrosis |
WO2005107461A2 (en) * | 2004-04-07 | 2005-11-17 | The General Hospital Corporation | Modulating lymphatic function |
JP2020513041A (en) | 2017-04-10 | 2020-04-30 | ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒルThe University Of North Carolina At Chapel Hill | Compounds, compositions and methods for pathogen inhibition and / or mucus modification |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5028627A (en) * | 1989-09-13 | 1991-07-02 | Cornell Research Foundation, Inc. | Method of using arginine derivatives to inhibit systemic hypotension associated with nitric oxide production or endothelial derived relaxing factor |
US5317040A (en) * | 1993-01-26 | 1994-05-31 | Washington University | Method for the treatment of pertussis with aminoguanidine |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5358969A (en) * | 1991-12-16 | 1994-10-25 | Washington University | Method of inhibiting nitric oxide formation |
-
1995
- 1995-07-13 WO PCT/GB1995/001657 patent/WO1996002245A1/en not_active Application Discontinuation
- 1995-07-13 EP EP95924472A patent/EP0768875A1/en not_active Withdrawn
- 1995-07-13 JP JP8504808A patent/JPH10502662A/en active Pending
- 1995-07-13 AU AU28966/95A patent/AU2896695A/en not_active Abandoned
- 1995-07-13 US US08/765,547 patent/US5859058A/en not_active Expired - Lifetime
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5028627A (en) * | 1989-09-13 | 1991-07-02 | Cornell Research Foundation, Inc. | Method of using arginine derivatives to inhibit systemic hypotension associated with nitric oxide production or endothelial derived relaxing factor |
US5317040A (en) * | 1993-01-26 | 1994-05-31 | Washington University | Method for the treatment of pertussis with aminoguanidine |
Non-Patent Citations (3)
Title |
---|
"Impairment of endothelium-dependent pulmonary artery relaxation in chronic obstructive lung disease", N.ENGL.J.MED., vol. 324, no. 22, pages 1539 - 47 * |
"Neural nitric oxide synthase is localized in extrinsic nerves regulating perireceptor processes in the chemosensory nasal mucosae of rats and humans", J.COMP.NEUROL., vol. 345, no. 1, 1 July 1994 (1994-07-01), pages 125 - 38 * |
"TNF-alpha stimulates mucin secretion and gene expression in airway epithelium in vitro", CHEST, vol. 107, no. 3, 3 March 1995 (1995-03-03), pages 133S - 135S * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6620848B2 (en) * | 1997-01-13 | 2003-09-16 | Smithkline Beecham Corporation | Nitric oxide synthase inhibitors |
US6274593B1 (en) | 1997-05-01 | 2001-08-14 | Smithkline Beecham P.L.C. | Substituted tetrahydro isoquinolines as modulators of dopamine D3 receptors |
WO2005041975A1 (en) * | 2003-10-31 | 2005-05-12 | Altana Pharma Ag | Use of bh4 for the treatment of respiratory diseases |
Also Published As
Publication number | Publication date |
---|---|
US5859058A (en) | 1999-01-12 |
EP0768875A1 (en) | 1997-04-23 |
JPH10502662A (en) | 1998-03-10 |
AU2896695A (en) | 1996-02-16 |
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